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Durham e-Theses
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The Influence of Carbon Dioxide on Cellular Cyclic Adenosine

COOK, ZARA,CHARLOTTE (2012) The Influence of Carbon Dioxide on Cellular Cyclic Adenosine
Doctoral thesis, Durham University.

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Inorganic carbon is fundamental to the physiology of all organisms, however elevated CO2 is generally
detrimental. Numerous class III adenylyl cyclases (AC) from both prokaryotic and mammalian
organisms have been shown to respond to inorganic carbon in vitro, however, at present there is
limited evidence in vivo. This thesis demonstrates in cellulo evidence that hypercapnia CO2 blunts
agonist induced cAMP signalling. The eect of CO2 is independent of changes in intracellular and
extracellular pH, independent of the mechanism used to activate the cAMP signalling pathway, and
is independent of the cell line employed. Through a combination of pharmacological and genetic
tools this eect of elevated CO2 on cAMP signalling is demonstrated to require Ca2+ ion release
from IP3 receptors in the endoplasmic reticulum. Consistent with these ndings, CO2 caused an
increase in cytoplasmic Ca2+ concentrations which require the presence of active IP3 receptors
and is absent under comparable acidotic conditions. Physiological relevance for this signalling
mechanism is demonstrated through activity of the sodium dependant proton exchanger NHE3.
This transporter exhibits well-characterised inhibition by cAMP dependant protein kinase PKA
to increase bicarbonaturia in vivo. Overall these results provide conclusive evidence of potentially
profound eects of inorganic carbon on intracellular cell signalling, which could lead to signicant
insight into the pathophysiology and treatment of numerous disorders including metabolic acidosis,
reperfusion injuries, acute lung injury and obesity.

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Keywords:CO2, Carbon Dioxide, NHE3, adenylyl cyclase, cAMP
Faculty and Department:Faculty of Science > Biological and Biomedical Sciences, School of
Thesis Date:2012
Copyright:Copyright of this thesis is held by the author
Deposited On:30 Nov 2012 11:02

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